The effects of phencyclidine (PCP), a psychotomimetic dissociative anesthetic, and several related drugs were examined on potassium currents in PC12 cells, a neuron-like clonal cell line derived from a rat pheochromocytoma. Whole-cell voltage clamp recordings demonstrated two kinetically distinct voltage-dependent potassium current components in these cells: a rapidly activating and inactivating component, IA, that was selectively eliminated by 4- aminopyridine and a slowly activating, minimally inactivating (sustained) component, IK, that was specifically blocked by tetraethylammonium. PCP (1-100 uM) produced a dose-dependent blockade of both IK and IA; however, at low doses the drug selectively reduced IK (IC50, 4 uM) with little effect on IA. The blockade of IK was voltage-dependent so that the degree of block decreased with increasing depolarization, indicating that the blocking mechanism is likely one in which the positively charged PCP molecule is drawn into the channel pore. PCP and related drugs were also found to selectively block IK in neurons cultured from the hippocampus of embryonic rats. Pharmacological studies indicated that this effect is probably mediated by "low affinity PCP" binding sites and not by "high affinity PCP" or sigma recognition sites to which PCP also binds. At very low doses (IC50, 0.6 uM), PCP selectively blocked N-methyl- D-asparate (NMDA) activated-cation currents in cultured hippocampal neurons. Structure-activity studies indicated that this effect was mediated by an effect at "high affinity PCP" binding sites. At low doses, PCP is a powerful anticonvulsant agent that may protect against seizures via a biological mechanism that is distinct from that of presently used anticonvulsants. However, at high doses the drug can induce convulsions. The present data are consistent with the hypothesis that the anticonvulsant activity of PCP is due to blockade of NMDA receptor-coupled channels whereas the convulsant effect results from blockade of voltage-dependent K + channels.